ORIGINAL ARTICLE

DOPPLER SONOGRAPHY OF THE BREAST CANCER

Muhammad Nawaz, Farzana Nawaz, Ahmad Nadeem Qureshi

ABSTRACT
Background: The purpose of this study was to determine how breast cancer vascularity, as revealed by power Doppler sonography, correlates with lymph node involvement and lymphatic vascular invasion. Research Methodology: This three years descriptive study from October 1, 2001 to September 30, 2004, was carried out at Department of Radiology, Khyber Teaching Hospital, Peshawar. Breast sonograms obtained during a 03 years period were retrospectively reviewed. Patients who underwent power Doppler sonography of solid masses of breast and had biopsy proven carcinoma composed our study population. Power Doppler findings were categorized according to the presence or absence of vessels. Pathologic findings were reviewed for lymph node involvement and lymphatic vascular invasion. Results: Of 176 patients with breast cancer, vessels were seen on power Doppler sonography in 128 (73). Of 126 patients who underwent lymph node dissection, Vessels were seen in 97 (77%). Lymph node involvement was seen in 42 (43%) of the 97 patients in whom vessels were seen and in three (10%) of the 29 in whom vessels were not seen. Of 150 patients examined for lymphatic vascular invasion, vessels were seen in 111 (74%) and not seen in 39 (26%) Lymphatic vascular invasion was seen in 47 (42%) of the 111 patients in whom vessels were seen and in 5 (13%) of the 39 in whom vessels were not seen. Tumor vascularity revealed by power Doppler sonography correlated strongly with detection of lymph node involvement and lymphatic vascular invasion, with sensitivities of 93% and 90%, respectively. However, the specificities were low, at 32% and 35% respectively. More important, patients with breast cancer in whom vessels were not revealed by power Doppler sonography also were unlikely to have lymph node involvement and lymphatic vascular invasion. Negative predictive values were 90% and 87% respectively. This study provides very good results. Conclusion: We conclude that power Doppler ultrasonography is a good screening tool for detecting vascularity of breast cancer masses. Key words: Power Doppler ultrasonography, Breast cancer, Vascularity.

INTRODUCTION
The incidence of breast cancer in the Pakistan has gradually increased over the last three decades1,2. Once breast cancer is diagnosed, information on the extent of tumor involvement is necessary to determine treatment options. In advanced cases of breast cancer, where the disease has spread, systemic therapy (including chemotherapy, hormonal therapy, or both) is needed. Although adjuvant therapy has also been shown to decrease the rate of recurrence in early cases of breast cancer (where the disease is local, without distant spread), local and regional treatments alone have also been shown to be curative3. Tumor size and lymph node status are important prognostic indicators of survival in patients with breast cancer4,5. Initial tumor growth and metastases are known to correlate with angiogenesis and neovascularization6,7. The ability of image-directed color and power Doppler sonography to assist in the diagnosis of breast carcinoma has been examined in a number

of studies8,9,10,11,12,13. Power Doppler sonography has certain advantages over color Doppler sonography that makes it more sensitive in the detection of vascular flow14,15. We have found that power Doppler sonography reveals vascularity in many breast cancers, with certain recurrent patterns of distribution8. In this study, we wanted to see if vascularity of breast cancer, as revealed by power Doppler sonography, correlates with lymph node involvement and lymphatic vascular invasion.

RESEARCH METHODOLOGY
We retrospectively reviewed the sonograms of all 176 patients with solid breast masses who presented to our department between October 1, 2001 and September 30, 2004. We included only patients who had undergone documented power Doppler assessment of the masses and in whom carcinoma had later on been proven by biopsy (n=176). All patients underwent breast sonography using an SA 8800 unit (Medison technology Korea) 14

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equipped with power Doppler imaging. A 5-10 MHz linear transducer was used. Each lesion was imaged with gray scale and power Doppler sonography in sagittal and transverse projections. The power Doppler settings were selected to optimize detection of small vessels within and around the tumor while suppressing background color, and the color box was sized to include the lesion and some surrounding normal breast tissue. Findings were categorized by the presence of absence of vessels. Power Doppler findings were considered positive when at least one vessel was associated with the solid breast mass. Many of the 176 breast cancers were initially diagnosed by sonographically guided core biopsy, although all ultimately underwent surgical excision. The pathology findings for these tumors were reviewed for tumor size and histological type. The categories of histologic type included ductal carcinoma in situ, invasive ductal carcinoma, invasive lobular carcinoma, invasive carcinoma with ductal and lobular features, and other invasive carcinomas. The histologic grade, ranging from I to III, was available for 153 lesions. Information on the presence or absence of lymphatic vascular invasion was available for 150 lesions. In patients who underwent lymph node dissection (n = 126), lymph node involvement was categorized as positive or negative for tumor. Tumor size was analyzed using Wilcoxons rank sum test. Other analyses were performed using the chi-square test.

These results, however, were not statistically significant (p< 0.1). The relationship between vascularity shown by power Doppler sonography and disease in lymph nodes was then examined and found to be statistically significant (p < .005). Vascularity was associated with lymph node involvement with sensitivity of 93%, a specificity of 32%, a positive predictive value of 43% and a negative predictive value of 90%. An examination of the relationship between vascularity shown by power Doppler sonography and lymphatic vascular invasion yielded similar results (p < .001). Vascularity was associated with lymphatic vascular invasion with a sensitivity of 90% a specificity of 35% a positive predictive value of 42% and a negative predictive value of 87%. To determine whether these results might be attributed solely to tumor size the data were then stratified into two categories tumors smaller than 2 cm and tumors 2 cm or larger . Two centimeters was chosen because this size is a criterion distinguishing stage I carcinomas from more advanced stages. The relationship between vascularity and lymph node involvement remained statistically significant (p < .05 for tumors < 2 cm and p < .03 for tumors > 2 cm). The relationship between vascularity and lymphatic vascular invasion also remained statistically significant (p < .04 for tumors < 2 cm and P < .03 for tumors > 2 cm). Of the three lesions with lymph node involvement for which no vessels were seen on power Doppler sonography, two had lymphatic vascular invasion and one did not. Of the five lesions with lymphatic vascular invasion for which no vessels were seen on power Doppler sonography, two had lymph node involvement, two did not, and one had an unknown lymph node status. Vascularity was also correlated with tumor grade. Tumors of all grades were more likely than not to show vessels on power Doppler sonography. However, the percentage of those showing vessels were higher for grade III tumors (89%) than for grades I and II tumors (76% and 66%, respectively). Of the 176 patients in our study population, mammograms were available to us for 160. Twenty of the solid masses seen sonographically were not seen on mammographic evaluation. These included one ductal carcinoma in situ, 12 invasive ductal carcinomas, five invasive lobular carcinomas, and two invasive carcinomas with ductal and lobular features. Of these twenty masses, power Doppler sonography showed vessels in 12 and no vessels in eight. The size of these masses ranged from 4 to 29 mm on sonography. Mammography of the 20 patients with these masses showed either dense or heterogeneously dense breast tissue; this density was be15

RESULTS RESULTS
The average patient age was 56 + 15 years (range 27-91 years). Sixty five percent (115/176) of the cases were invasive ductal carcinoma, and 10% (18/176) were invasive lobular carcinoma. Invasive carcinoma with mixed ductal and lobular features composed 15% (26/176) of the cases. Six percent had ductal carcinoma in situ. Of the 4% remaining cases (7 patients) of invasive carcinoma (4%), four were papillary, two mucinous, and one tubular. Of the 176 breast cancers, 128 (73%) showed vascularity and 48 (27%) showed no vascularity on power Doppler sonography. The average size of the lesions in which power Doppler sonography revealed vessels was 21 mm (SD, 15 mm; range, 7-80 mm). The average size of the lesions in which vessels were not revealed was 14 mm (SD, 14 mm; range, 3-55 mm). The tumors with vessels were larger than those without (p<0.01); however, the two categories overlapped. The presence or absence of vascularity was compared with histologic tumor type. Invasive carcinoma that was ductal or had ductal features was more likely to show vessels on power Doppler sonography than was purely lobular carcinoma, other invasive carcinomas, and ductal carcinoma in situ.

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lieved to be a major contributing factor as to why these lesions were mammographically occult. The remainder of the 140 lesions showed some abnormality on mammography.

DISCUSSION
Tumor growth and metastasis depend on angiogenesis and neovascularization16,17. Two major clinical methods for assessing tumor vascularity are micro vessel density (on a microscopic level) and Doppler sonography (on a macroscopic level). Weidner et al 18 reported an association between micro vessel density and outcome in patients with breast cancer. Stems et al13 examined the micro vessel density and the vascularity revealed by Doppler sonography of 207 invasive ductal carcinomas. They found no significant difference in the mean micro vessel density when comparing tumors showing vascularity with those showing no vascularity. However, when the micro vessel density was more than 80 vessels per 250x field, the tumors were significantly more likely to be seen as vascular on Doppler sonography 13. Other studies have assessed Doppler sonography alone to determine if vascularity revealed by Doppler sonography correlates with lymph node metastases10,19-21. Seventy three percent (128) of the breast carcinomas in our study population showed vessels on power Doppler sonography; This percentage is similar to that of other studies using power Doppler, which have shown vascularity in 73-84% of breast tumors 8,9 . Although we did not find a correlation between vascularity and histologic tumor type, we did find that purely lobular invasive carcinoma was less likely to show vascularity than was invasive carcinoma that was purely ductal or had ductal features. This finding was also shown in our prior work with power Doppler sonography 8. Dixon et al22 also noted that in their series of 32 cases of breast cancer, invasive lobular carcinoma was least likely to show vascularity on color Doppler sonography. Lymph node status is a major prognostic indicator in patients with breast cancer. However, axillary lymph node dissection is responsible for much of the morbidity associated with breast surgery23,24,25. An alternative that has been studied is sentinel node excision. A multicenter study on sentinel node biopsy26 showed that it could predict the presence or absence of axillary node metastases. However, those researchers also found that the success rate varied depending on patient age and location of the primary carcinoma, as well as from surgeon to surgeon. A potential noninvasive method that we studied to assess the presence or absence of lymph node metastases was power Doppler sonography. A large number of cancerous breast tumors are shown to

have vascularity on power Doppler sonography making the correlation with lymph node involvement high (sensitivity of 93% in our study) and the specificity low (32% in our study). However, of the cases showing no tumor vascularity on power Doppler sonography, 90% had no lymph node involvement. By comparison, of those that did show vascularity on power Doppler sonography, 57% had no lymph node involvement. Kuijpers et al 19, in using pulsed Doppler sonography of primary tumors to assess lymph node status, defined a positive Doppler signal as a Doppler shift frequency of more than 1 kHz using a 5 MHz insolating frequency. For 53 of the 57 cancer patients in their group, the lymph node status was known. The Doppler signal findings for predication of lymph node involvement had a sensitivity of 84%, a specificity of 56%, a positive predictive value of 51%, and a negative predictive value of 86%. Kubek et al21 examined 53 benign and 33 malignant breast masses for a rim sign, which was defined as a curvilinear or branching pattern a the periphery of a mass on color Doppler sonography. They found the sign in 30% of the benign and 61% of the malignant breast masses in their series. In the subset of patients with malignant masses, lymph node involvement was present in 50% of the patients with a positive rim sign and 10% of the patients with a negative rim sign. Our study, which included more patients but used a different Doppler technique, had results similar to those of Kuijpers et al19 and Kubek et al21. Stems et al13 also showed significant differences in rates of lymph node involvement in breast cancers with and without vascularity shown by Doppler sonography. In their study of 207 patients with invasive ductal carcinoma, lymph node involvement was present in 27 of 51 lesions showing vessels on Doppler sonography (positive predictive value of 53%) and 47 of 156 lesions showing no vessels on Doppler sonography (also negative rate of 30%). Yet other studies using color Doppler sonography have shown no correlation between tumor vascularity and lymph node status10,20. Tumors may spread to the lymph nodes through either a hematogenous route or lymphatic drainage. The latter was our reason for seeking a correlation between power Doppler vascularity and lymphatic vascular invasion. Our results were similar to those for lymph node involvement. For 74% (111/150) of the lesions for which we had information on lymphatic vascular invasion, power Doppler sonography revealed vessels. This figure resulted in a high sensitivity (90%) but a low specificity (35%). However, in the subset of patients for whom power Doppler sonography revealed no vessels, only five of 39 and 16

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lymphatic vascular invasion, resulting in a negative predictive value of 87%. Cosgrove et al10, in their study on color Doppler sonography of breast diseases, found 37 breast cancers. In this small group, no correlation was found between vascularity and lymphatic vascular invasion. Unlike prior investigators13,19,21, we found a statistically significant difference in tumor size between the group with vascularity and the group without, although overlap existed. However, the correlation between vascularity and lymph node involvement or lymphatic vascular invasion remained statistically significant among tumors smaller than 2 cm and tumors 2 cm or larger, confirming that size was not the only factor contributing to our findings. Although the grade III tumors in our group were more likely to show vascularity, the presence or absence of vascularity was not helpful in predicting grade. Other reports also have failed to show a correlation between Doppler sonography and tumor grade10,12,22. In summary, power Doppler sonography reveals blood vessels in most breast cancers. Invasive ductal carcinoma and invasive carcinoma with ductal and lobular features were more likely to show vascularity than was purely invasive lobular carcinoma, other invasive carcinomas, and ductal carcinoma in situ. Power Doppler vascularity was not helpful in predicting tumor grade and was highly sensitive but not specific in determining lymph node involvement and lymphatic vascular invasion. More important, we found that breast cancers showing no vessels on power Doppler sonography were much less likely to have associated lymph node involvement or lymphatic vascular invasion than were tumors showing vessels, with negative predictive values of 90% and 87%, respectively.

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Burns PN, Halliwell, Wells PNT, Webb AJ. Ultrasonic Doppler studies of the breast. Ultrasound Med Biol 1982; 8: 127-143. Raza S. Baum JK. Solid breast lesions: evaluation by power Doppler ultrasound. Radiology 1997; 203: 164-168. Birdwell RL, Ikeda DM, Jeffrey SS, Jeffrey RB Jr. Preliminary experience with power Doppler imaging of solid breast masses. AJR 1997; 169: 703-707. Cosgrove DO, Kedar RP Bamber JC et al. Breast , diseases: color Doppler US in differential diagnosis. Radiology 1993: 189:99-104. Lee SK, Lee T, Lee KR, Su YG, Liu TJ. Evaluation of breast tumors with color Doppler imaging: a comparison with image directed Doppler ultrasound J. Clin Ultrasound 1995; 23: 367-373. McNicholas MMJ, Mercer PM, Miller JC, McDermott EWM, OHiggins NJ, MacErlean DP Color Doppler . sonography in the evaluation of palpable breast masses. AJR 1993: 161: 765-771. Stems EE, SenGupata S, Saunders F, Zee B. Vascularity demonstrated by Doppler ultrasound and immunohistochemistry in invasive ductal carcinoma of the breast. Breast Cancer Res Treat 1996; 40: 197-203. Bude RO, Rubin JM, Adler RS. Power versus conventional color Doppler sonography: comparison in the depiction of normal intrarenal vasculature. Radiology 1994; 192: 777-780. Rubin JM, Bude RO, Carson PL, Bree RL, Adler RS. Power Doppler US: a potentially useful alternative to mean frequency based color Doppler US. Radiology 1994;190:853-856. Folkman J. Tumor angiogenesis In: Mendelson J, Howley PM, Israel MA, Liotta LA, eds. The molecular basis of cancer. Philadelphia: Saunders, 1995: 206-232. Gasparini G, Harris AL. Clinical importance of the determination of tumour angiogenesis in breast carcinoma: much more than a new prognostic tool. J. Clin Oncol 1995; 13: 765-782. Weidner N, Semple U, Welch WR, Folkman J. Tumour angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl. J. Med. 1991; 324: 1-8. Kuijpers TJA, Obdeijn AIM, Kruyt RH, Oudkerk M, Solid breast neoplasms: differential diagnosis with pulsed Doppler ultrasound. Ultrasound Med Biol 1994; 20: 517-520. Holcombe C, Pugh N, Lyons K, Douglas Jones A, Mansel RE, Horgam K. Blood flow in breast cancer and fibroadenoma estimated by colour Doppler ultrasonography. Br. J. Surg. 1995; 82: 787-788. Kubek KA, Chan L, Frazier TG, Color Doppler flow as an indicator of nodal metastasis in solid breast masses. J. Ultrasound Med. 1996; 15: 835-841.

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Address for Correspondence: Dr. Muhammad Nawaz Department of Radiology, Khyber Teaching Hospital, Peshawar. E-mail: nawazrad@yahoo.com

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